PhoP: a missing piece in the intricate puzzle of Mycobacterium tuberculosis virulence.
Inactivation of the transcriptional regulator PhoP results in Mycobacterium tuberculosis attenuation. Preclinical testing has shown that attenuated M. tuberculosis phoP mutants hold promise as safe and effective live vaccine candidates. We focused this study to decipher the virulence networks regulated by PhoP. A combined transcriptomic and proteomic analysis revealed that PhoP controls a variety of functions including: hypoxia response through DosR crosstalking, respiratory metabolism, secretion of the major T-cell antigen ESAT-6, stress response, synthesis of pathogenic lipids and the M. tuberculosis persistence through transcriptional regulation of the enzyme isocitrate lyase. We also demonstrate that the M. tuberculosis phoP mutant SO2 exhibits an antigenic capacity similar to that of the BCG vaccine. Finally, we provide evidence that the SO2 mutant persists better in mouse organs than BCG. Altogether, these findings indicate that PhoP orchestrates a variety of functions implicated in M. tuberculosis virulence and persistence, making phoP mutants promising vaccine candidates.
Gonzalo-Asensio
Jesús
J
Grupo de Genética de Micobacterias, Departamento de Microbiología, Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain.
Mostowy
Serge
S
Harders-Westerveen
Jose
J
Huygen
Kris
K
Hernández-Pando
Rogelio
R
Thole
Jelle
J
Behr
Marcel
M
Gicquel
Brigitte
B
Martín
Carlos
C
D000818:Animals; D000942:Antigens, Bacterial; D001500:BCG Vaccine / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015687:Cell Hypoxia / Q000235:genetics; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D050356:Lipid Metabolism / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity* / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000235:genetics; D040901:Proteomics; D014376:Tuberculosis / Q000382:microbiology / Q000473:pathology / Q000662:veterinary; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
D000942:Antigens, Bacterial; D001500:BCG Vaccine; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D037521:Virulence Factors; C061064:PhoP protein, Bacteria